Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism

Abstract

BACKGROUND. Beige and brown adipose tissue (BAT) are associated with improved metabolic homeostasis. We recently reported that the β3AR agonist mirabegron induced beige adipose tissue in obese insulin resistant subjects, and this was accompanied by improved glucose metabolism. Here we evaluated pioglitazone treatment with a combination pioglitazone and mirabegron treatment, and compared these to previously published data evaluating mirabegron treatment alone. Both drugs were used at FDA-approved dosages. METHODS. We measured BAT by PET CT scans, beige adipose tissue by immunohistochemistry, and comprehensively characterized glucose and lipid homeostasis and insulin sensitivity by euglycemic clamp and oral glucose tolerance tests. Subcutaneous white adipose tissue, muscle fiber type composition and capillary density, lipotoxicity, and systemic inflammation were evaluated by immunohistochemistry, gene expression profiling, mass spectroscopy, and ELISAs. RESULTS. Treatment with pioglitazone or the combination of pioglitazone and mirabegron increased beige adipose tissue protein marker expression and improved insulin sensitivity and glucose homeostasis, but neither treatment induced BAT in these obese subjects. When the magnitude of the responses to the treatments were evaluated, mirabegron was found to be the most effective at inducing beige adipose tissue. Although monotherapy with either mirabegron or pioglitazone induced adipose beiging, combination treatment resulted in less beiging than either alone. The three treatments also had different effects on muscle fiber type switching and capillary density. CONCLUSION. The addition of pioglitazone to mirabegron treatment does not enhance beiging or increase BAT in obese, insulin-resistant research participants. TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176.

Brown Adipose Tissue—A Translational Perspective

“…Another open-label study showed that 12-week mirabegron treatment (50 mg/day) of healthy individuals led to increased WAT expression of UCP1, TMEM26, CIDEA proteins, and phosphorylation of hormone-sensitive lipase on serine 660, suggesting considerable browning of subcutaneous WAT with prolonged treatment with mirabegron ( 681 ). Another study by the same group extended these findings by showing that pioglitazone 30 mg/day for 12 weeks in overweight or obese participants also resulted in WAT browning, but that combined treatment with mirabegron + pioglitazone actually reduced WAT browning marker levels compared to monotherapy ( 682 ). None of the treatment arms led to increased cold-induced BAT 18 FDG uptake.…”

“…However, pioglitazone treatment for 28 days in humans did not induce WAT browning and even led to reduced cold-induced BAT glucose uptake in 1 study ( 635 ). Another study found a significant increase in subcutaneous WAT browning markers after 12 weeks of treatment with pioglitazone 30 mg per day in overweight or obese individuals, but again without an increase in cold-induced BAT glucose uptake ( 682 ). The clinical significance of WAT browning for the marked antidiabetic effects of PPAR-γ agonists is unclear at the moment, whereas the metabolic activation of BAT through PPAR-γ agonists is unlikely in humans.…”

Macrophages expressing uncoupling protein 1 increase in adipose tissue in response to cold in humans

“…The role of macrophages in adipose tissue under different physiological settings such as obesity has been widely studied 25 , 26 . Macrophages are key mediators of low grade adipose tissue inflammation in obesity, promoting insulin resistance 26 .…”

Pioglitazone for optimisation of clinical nutrition therapy in the critically ill patient: A Systematic Review

“…One study used Computer Tomography to examine muscle mass and body composition, and four used Dual Energy X-ray Absorptiometry (DEXA). In 44 patients, appendicular lean mass measured by CT was unaffected by low dose pioglitazone (15mg 3 weeks followed by 30mg for 3 weeks) 23 , and a 30mg/12 week regimen had no effect in 12 patients 25 . In 2 studies of 23 patients randomised to pioglitazone 45mg/10-16 weeks, an increase in lean body mass of 1.8-1.92kg was seen using Dual-energy X-ray absorbtiometry 26,27 .…”